REVIEW Standardization of the infusion Official Publication of the Instituto Israelita de Ensino e Pesquisa Albert Einstein sequence of antineoplastic drugs used in the treatment of breast and ISSN: 1679-4508 | e-ISSN: 2317-6385 colorectal cancers Padronização da ordem de infusão de medicamentos antineoplásicos utilizados no tratamento dos cânceres de mama e colorretal

Amanda Alves da Silva1, Juliane Carlotto1, Inajara Rotta1

1 Setor de Farmácia Hospitalar, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil.

DOI: 10.1590/S1679-45082018RW4074

❚❚ABSTRACT The definition of antineoplastic administration sequences can help planning of therapeutic regimens in a more rational way, and thus optimize effects on patients, increasing efficacy and reducing toxic effects. In this way, this study aimed to evaluate the infusion order of antineoplastic agents of the main therapeutic protocols used in the treatment of colorectal and breast cancer which are used in a tertiary hospital, identifying possible interactions dependent on the infusion sequence. For the definition of protocols adopted in the hospital, medical prescriptions were used in the period of January to March 2016 and a literature review was conducted to search for studies assessing the sequence of administering the selected regimens. The databases used were SciELO, LILACS and MEDLINE, in addition to Micromedex Solutions® and UpToDate®. A total of 19 protocols were identified for antineoplastic therapy, 11 for colorectal cancer and 8 for breast How to cite this article: cancer. The selected articles provided evidence for administration order of 19 protocols, and three Silva AA, Carlotto J, Rotta I. Standardization of the infusion sequence of antineoplastic protocols did no report relevance of infusion sequence. Sequence-dependent interactions were drugs used in the treatment of breast and mainly related to toxicity, pharmacokinetics and efficacy of the drug combination. The definition of colorectal cancers. einstein (São Paulo). the infusion sequence has a great impact on the optimization of therapy, increasing efficacy and 2018;16(2):eRW4074. safety of the protocols containing combined antineoplastic therapies. Corresponding author: Inajara Rotta Rua General Carneiro, 181 − Alto da Glória Keywords: Administration, intravenous; Antineoplastic agents/administration & dosage; Breast Zip code: 80060-900 − Curitiba, PR, Brazil neoplasms; Colorectal neoplasms Phone: (55 41) 3360-7939 E-mail: [email protected] Received on: ❚❚RESUMO Mar 30, 2017 A definição de sequências de administração de antineoplásicos pode proporcionar o planejamento Accepted on: Nov 6, 2017 dos esquemas terapêuticos de forma mais racional e, assim, otimizar o efeito da quimioterapia nos pacientes, aumentando a eficácia e reduzindo o aparecimento de efeitos tóxicos. Desta forma, Conflict of interest: none. o objetivo deste estudo foi avaliar a ordem de infusão dos antineoplásicos constituintes dos principais protocolos terapêuticos para o tratamento dos cânceres de mama e colorretal utilizados Copyright 2018 em um hospital terciário, identificando possíveis interações dependentes da sequência de infusão. Para definição dos protocolos adotados na Instituição, foram utilizadas as prescrições no período This content is licensed under a Creative Commons de janeiro a março de 2016, sendo então realizada uma revisão de literatura, para buscar estudos Attribution 4.0 International License. que avaliaram a sequência de administração dos esquemas selecionados. Para tanto, as seguintes

einstein (São Paulo). 2018;16(2):1-9 1 Silva AA, Carlotto J, Rotta I bases de dados foram utilizadas: SciELO, LILACS e MEDLINE, além via the cytochrome P450 pathway (CYP), and other das plataformas Micromedex Solutions® e UpToDate®. Foram chemotherapeutic drugs (e.g. and platinum identificados 19 protocolos para terapia antineoplásica, sendo agents) present high levels of protein binding. Moreover, 11 para câncer colorretal e 8 para câncer de mama. Os artigos many chemotherapeutic drugs have specific mechanisms selecionados forneceram evidências para ordem de administração de of action during the , and can increase 19 protocolos, e em 3 protocolos, não foi evidenciada a relevância da sequência infusional. As interações dependentes de sequência foram cytotoxicity or antagonize the mechanism of the (6) principalmente relacionadas à toxicidade, farmacocinética e eficácia second agent. da combinação de fármacos. A definição da sequência infusional Recognizing these pharmacokinetic interactions possui grande impacto na otimização da terapia, aumentando a between drugs is important to optimize doses of cytotoxic eficácia e a segurança dos protocolos, contendo terapias combinadas agents in combined chemotherapy. Many drugs called de antineoplásicos. “cell cycle specific drugs” (CCS) are effective against cancer and act on cells that are in the cell cycle. A Descritores: Administração intravenosa; Antineoplásicos/administração second group of agents called “cell cycle nonspecific & dosagem; Neoplasias da mama; Neoplasias colorretais drugs” (CCNS) are able to kill tumor cells, regardless of their being in the cell cycle or at rest.(7) Regarding the infusion order, if the specific antineoplastic agents ❚❚INTRODUCTION are administered before nonspecific cycles, maximized Cancer is a worldwide public health issue. In 2012, effect in cells with high cell division rates, such as there were 14.1 million cases of cancer around the neoplastic cells, is theoretically expected. The reason world, and it is estimated this number will reach 24 is when the cell cycle is interrupted at the time of (1) million, in 2025. According to the Instituto Nacional division, nonspecific agents can more easily act in the de Câncer “José Alencar Gomes da Silva” (INCA), in DNA.(8) Furthermore, it is argued that it is preferable 2016/2017, Brazil had approximately 600 thousand new to first administer the vesicant antineoplastic drug, cases of cancer; in that, breast (28.1%) and colorectal considering vascular integrity decreases with time. cancer (8.6%) were the most prevalent among It is therefore advantageous to infuse the vesicant women, and prostate (28.6%), tracheal, bronchial antineoplastic agent when the vein is more stable and and lung (8.1%), and colorectal (7.8%), in males. less irritated.(9) Non-melanoma skin cancer was not included in this As a focus of this study, we have chosen to work with estimate and is the most prevalent in both sexes.(2) protocols used for treatment of breast and colorectal Colorectal cancer is among the five most frequent cancers, for being the most prevalent in women (breast neoplasms, and its incidence is not homogeneous and colorectal) and are among the most prevalent throughout Brazil; it is more prevalent in the South in men (colorectal), especially in the South and and Southeast regions of the country.(3) Southeast regions of Brazil. The combination of several drugs with different Even though many reports have been published mechanisms of action is an effective strategy in on this topic, there are no studies containing the cancer treatment and provides many benefits. First, evaluation of infusion sequence for all protocols used in the association of two or more drugs with different antineoplastic therapy. Therefore, to define the infusion mechanisms of actions can delay cell mutations and sequence, we must often rely on pharmacokinetic the process of adjustment to cancer. Second, the and pharmacodynamic evaluations and on drug synergistic effect of the drugs, that is, the combined characteristics. In the literature, there is not yet one action of leading to potentiated biological single source compiling the ideal administration effect.(4) The pharmacological mechanisms involved sequences for the main protocols used in antineoplastic in the process of interactions among intravenous therapy. solutions are basically pharmacokinetic interactions (involving factors that accelerate or delay absorption, distribution, metabolization and elimination of the ❚❚OBJECTIVE drugs used) and pharmacodynamic interactions (factors To identify interactions that depend on the infusion leading to dysfunction in the pharmacological sequence to establish recommendations for the receptor binding).(5) Several antineoplastic agents (e.g. administration of antineoplastic agents in protocols , , , etc.) are metabolized used in breast and colorectal cancer treatments.

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❚❚METHODS Table 1 shows therapeutic protocols used at the This is a literature review study about the evaluation of organization for breast and colorectal cancer with the infusion sequence of antineoplastic drugs in protocols respective number of patients for whom they were used in colorectal and breast cancer treatments, prescribed. employed in a tertiary hospital in the city of Curitiba (State of Paraná). To define therapeutic protocols containing antineoplastic drug combinations used at the organization, we analysed medical prescriptions of Table 1. Therapeutic protocols adult patients seen at the oncology outpatient clinic. Protocols n (%) We selected prescriptions given between January AC* 48 (27.53) and March 2016 that included the combinations of FLOX† 19 (10.67) antineoplastic drugs used in breast and colorectal B-FOL† 18 (10.11) cancer treatment. We excluded prescriptions containing + 17 (9.55) regimens in which the antineoplastic drugs had not MAYO‡ 15 (8.43) been administered on the same day, or those that TC§ 10 (5.62) included only one antineoplastic agent, since the Cisplatin + 9 (5.06) objective of the study was to determine the + 7 (3.93) infusion sequence. Gemcitabine + docetaxel 7 (3.93) Based on the therapeutic protocols selected from FOLFIRI¶ 6 (3.37) medical prescriptions, we conducted a literature review FOLFOX|| 5 (2.81) to search for studies evaluating the administration IFL¶ 2 (1.12) sequence of the selected regimens. To that end, MC DONALD‡ 2 (1.12) we used the databases Scientific Electronic Library Paclitaxel + pamidronate 2 (1.12) Online (SciELO), Latin American and Caribbean Health Sciences Literature (LILACS) and MEDLINE M-FOLFOX 2 (1.12) (PubMed). The keywords to identify studies related to Paclitaxel + zoledronic acid 2 (1.12) the theme included any combination of the protocol Docetaxel + pamidronate 1 (0.56) name and/or antineoplastic drug, with the English Trastuzumab + pertuzumab 1 (0.56) words “administration”, “sequencing” or “interactions”. CAF# 1 (0.56) Additionally, we used the software Micromedex Solutions® Cisplatin + paclitaxel 1 (0.56) and UpToDate® to collect information on the drugs FOLFOXIRI** 1 (0.56) and on possible drug interactions. We included all Trastuzumab + paclitaxel 1 (0.56) articles about protocols of interest, giving preference to * Protocol AC was composed of doxorubicin and ; † protocols FLOX and B-FOL were composed of , folinic acid and fluorouracil, in different combination regimens; protocols MAYO and MC DONALD included those conducted in humans and excluding the studies folinic acid and fluorouracil; § protocol TC was composed of docetaxel and cyclophosphamide; ¶ protocols FOLFIRI and IFL comprised irinotecan, folinic acid and fluorouracil in different combination regimens; || protocol FOLFOX was composed containing protocols of drugs not administered on the of oxaliplatin, folinic acid and fluorouracil; # protocol CAF comprised doxorubicin, fluorouracil and cyclophosphamide; same day of treatment. ** protocol FOLFOXIRI included irinotecan, oxaliplatin, folinic acid and fluorouracil. For situations without a clearly established infusion sequence or with disagreement among authors, we evaluated pharmacokinetics, pharmacodynamics and characteristics of each antineoplastic drug to define the most appropriate sequence. This study was approved In total, 178 patients used 22 different protocols by the Research Ethics Committee, protocol 1.776.532, containing a combination of antineoplastic drugs. CAAE: 59998016.0.0000.0096. The bibliographic search yielded 36 articles that were the basis to evaluate these protocols. The selected articles brought some evidence towards the ❚❚RESULTS administration sequence of 19 protocols (Table 2), while A total of 408 prescriptions containing treatment for 3 protocols there was no evidence of relevance in protocols for colorectal and breast cancer were the infusion sequence (Table 3). Interactions dependent evaluated. Most patients were female (65.8%) and on the sequence were mainly related to toxicity, mean age was 53.56 years. pharmacokinetics and efficacy of drug combination.

einstein (São Paulo). 2018;16(2):1-9 3 Silva AA, Carlotto J, Rotta I

Table 2. Suggested sequence for the therapeutic protocol and reasons for infusion order Suggested sequence Protocol Agent Reasons for suggestion First Second Third Fourth AC Doxorubicin Cyclophosphamide - - Compatible in Y(10) CCNS(7) CCNS(7) Cyclophosphamide is a prodrug catalyzed directly by cytochrome P450, Vesicant(9) mainly through CYP2B6.(11) Doxorubicin is a (moderate) inhibitor of the same enzyme.(12) To avoid delayed plasma clearance of doxorubicin due to cyclophosphamide metabolism, it is recommended to infuse doxorubicin before cyclophosphamide.(5) CAF Doxorubicin Fluorouracil Cyclophosphamide - Compatible in Y(10) CCNS(7) CCS(7) CCNS(7) Fluorouracil acts in specific cell cycle phases, while doxorubicin Vesicant(9) and cyclophosphamide are CCNS.(7) However, doxorubicin has a high tissue vesicant potential, which reinforces the importance of it being administered first.(9) Cyclophosphamide is a prodrug catalyzed directly by cytochrome P450, especially through CYP2B6.(11) Doxorubicin is a (moderate) inhibitor of the same enzyme.(12) To avoid delayed plasma clearance of doxorubicin due to cyclophosphamide metabolism, it is recommended to infuse doxorubicin before cyclophosphamide.(5) Regarding fluorouracil and cyclophosphamide, it has been observed that fluorouracil sensitizes the DNA so it can be attacked by alkylating agents.(13) Cisplatin + Gemcitabine Cisplatin - - Compatible in Y(10) Gemcitabine CCS(7) CCNS(7) Gemcitabine is a CCS drug while cisplatin is CCNS, which justifies this infusion sequence. Also, gemcitabine administration (4 or 24 hours) before cisplatin administration proved less toxic, causing less leukopenia.(14) Cisplatin + Cisplatin Irinotecan - - Compatible in Y(10) irinotecan CCNS(7) CCS(7) Irinotecan is a CCS drug, while cisplatin is CCNS. However, with previous administration of cisplatin, there is an increase in the synergistic effect, with the presence of toxicity regardless of the administration sequence.(15,16) Cisplatin + Paclitaxel Cisplatin - - Compatible in Y(10) paclitaxel CCS(7) CCNS(7) Paclitaxel is a CCS drug, whereas cisplatin is CCNS, which justifies this infusion sequence.(7) When cisplatin is administered first, paclitaxel clearance is reduced, and myelosuppression is more severe. It has been suggested that this decrease in paclitaxel clearance, after cisplatin, may be due to cytochrome P450 inhibition, which is responsible for paclitaxel metabolism.(17) Docetaxel + Docetaxel Pamidronate - - Compatible in Y(10) pamidronate CCS(7) No studies were found on administration order. The recommendation is to administer docetaxel first, considering pamidronate may cause nephrotoxicity, which manifests as nephritic syndrome, kidney function deterioration and renal failure, which could alter docetaxel excretion.(18) FOLFIRI Irinotecan Fluorouracil Fluorouracil - Incompatible in Y (irinotecan – fluorouracil)(10) CCS(7) + Folinic CCS(7) (bolus) CCS(7) (continuous Folinic acid stabilizes thymidylate synthase when administered before acid infusion – 46 hours) fluorouracil, increasing the efficacy and cytotoxicity of the latter.(19,20) (60 minutes prior) Moreover, for better action of folinic acid, a minimum 60-minute period is required for drug distribution and intracellular metabolism.(5) We observed a synergistic effect when there was previous exposure to irinotecan, intensifying fluorouracil-induced DNA damage.(21) According to a study by Falcone et al., toxicity was affected by the administration sequence of irinotecan and fluorouracil, with acceptable toxicity when irinotecan was followed by fluorouracil.(22) To provide faster patient care, the concomitant initial infusion of irinotecan and folinic acid was proposed, followed by fluorouracil in bolus and fluorouracil in continuous infusion.(8) It is worth mentioning the importance of cleaning the Y system between the infusions of irinotecan and fluorouracil, due to incompatibility. continue...

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...Continuation Table 2. Suggested sequence for the therapeutic protocol and reasons for infusion order Suggested sequence Protocol Agent Reasons for suggestion First Second Third Fourth FOLFOXIRI Irinotecan Oxaliplatin Fluorouracil - Incompatible in Y (irinotecan – fluorouracil)(10) CCS(7) CCNS(7) CCS(7) Not tested in Y (fluorouracil – oxaliplatin)(10) + (continuous infusion– Irinotecan in a prodrug and thus requires hepatic microsomal activation. Folinic acid 46 hours) Therefore, whenever possible, this type of drug should be prioritized in (60 minutes prior) multiple infusions.(5) Also, some studies demonstrated there may be an increase in cholinergic side effects of irinotecan when administered after oxaliplatin.(23) Dodds et al., observed the cholinergic effects of irinotecan are manifested by inhibiting acetylcholinesterase.(24) Similarly to other alkylating agents, oxaliplatin can also inhibit this enzyme, which can potentiate the cholinergic effects of irinotecan. Regarding the combination between oxaliplatin and fluorouracil, Qin et al. observed in vitro synergistic effect, i.e., apoptosis was more prominent when cells were treated with oxaliplatin first and then with fluorouracil.(25) Furthermore, some studies demonstrated oxaliplatin can inhibit the main enzyme of fluorouracil metabolism (dihydropyrimidine dehydrogenase).(26) A synergistic effect was observed when there was previous exposure to irinotecan, intensifying DNA damage induced by fluorouracil.(21) According to a study by Falcone et al., toxicity was affected by the administering sequence of irinotecan and fluorouracil, with acceptable toxicity when irinotecan was followed by fluorouracil.(22) Folinic acid stabilizes thymidylate synthase when administered before fluorouracil, increasing efficacy and cytotoxicity of the latter.(19,20) Moreover, for better action of folinic acid, a minimum 60-minute period is required for the distribution of the drug and intracellular metabolism.(5) It is worth mentioning the importance of cleaning the Y system between the infusions of irinotecan and fluorouracil, due to incompatibility. FLOX/B-FOL Oxaliplatin Folinic acid Fluorouracil - Not tested in Y (fluorouracil – oxaliplatin).(10) CCNS(7) (60 minutes prior) CCS(7) Folinic acid stabilizes thymidylate synthase when administered before fluorouracil, increasing efficacy and cytotoxicity of the latter.(19,20) Moreover, for better action of folinic acid, a minimum 60-minute period is required for distribution of the drug and intracellular metabolism.(5) Regarding the combination between oxaliplatin and fluorouracil, Qin et al. observed in vitro synergistic effect, i.e., apoptosis was more prominent when cells were treated with oxaliplatin first and then with fluorouracil.(25) Furthermore, some studies demonstrated that oxaliplatin can inhibit the main enzyme of fluorouracil metabolism (dihydropyrimidine dehydrogenase).(26) FOLFOX Oxaliplatin Fluorouracil Fluorouracil Not tested in Y (fluorouracil – oxaliplatin).(10) CCNS(7) CCS(7) (bolus) CCS(7) (continuous Folinic acid stabilizes thymidylate synthase when administered + infusion – 46 hours) before 5-FU, increasing the efficacy and cytotoxicity of the latter.(19,20) Folinic acid Moreover, for better action of the folinic acid, a minimum 60-minute (60 minutes prior) period is required for distribution of the drug and intracellular metabolism.(5) Regarding the combination between oxaliplatin and 5-FU, Qin et al., observed in vitro synergistic effect; apoptosis was more prominent when cells were treated with oxaliplatin first and then with 5-FU.(25) Furthermore, some studies demonstrated oxaliplatin can inhibit the main enzyme of 5-FU metabolism (dihydropyrimidine dehydrogenase).(26) To provide more efficient patient care, concomitant initial infusion of oxaliplatin and folinic acid was proposed, followed by fluorouracil in bolus and fluorouracil in continuous infusion.(27) continue...

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...Continuation Table 2. Suggested sequence for the therapeutic protocol and reasons for infusion order Suggested sequence Protocol Agent Reasons for suggestion First Second Third Fourth IFL Irinotecan Folinic acid Fluorouracil - Incompatible in Y (irinotecan – fluorouracil).(10) CCS(7) (60 minutes prior) CCS(7) Folinic acid stabilizes thymidylate synthase when administered before fluorouracil, increasing the efficacy and cytotoxicity of the latter.(19,20) Moreover, for better action of the folinic acid, a minimum 60-minute period is required for distribution of the drug and intracellular metabolism.(5) A synergistic effect was observed when there was previous exposure to irinotecan, intensifying DNA damage induced by fluorouracil.(24) According to a study by Falcone et al., toxicity was affected by the administering sequence of irinotecan and fluorouracil, with acceptable toxicity when irinotecan was followed by fluorouracil.(22) It is worth mentioning the importance of cleaning the Y system between the infusions of irinotecan and fluorouracil, due to incompatibility. MAYO/ McDonald/ Folinic acid Fluorouracil - - Compatible in Y(10) fluorouracil + (60 minutes prior) CCS(7) Folinic acid stabilizes thymidylate synthase when administered folinic acid before fluorouracil, increasing the efficacy and cytotoxicity of the latter.(19,20) Moreover, for better action of the folinic acid, a minimum 60-minute period is required for distribution of the drug and intracellular metabolism.(5) Paclitaxel + Paclitaxel Zoledronic acid - - Compatible in Y(10) zoledronic acid CCS(7) Increase of synergistic effects due to increased apoptosis.(28) Paclitaxel + Paclitaxel Pamidronate - - Compatible in Y(10) pamidronate CCS(7) No studies were found describing an administration sequence. The recommendation is to administer paclitaxel first, considering pamidronate can cause nephrotoxicity, which manifests as nephritic syndrome, kidney function deterioration and renal failure, which could alter paclitaxel excretion.(18) TC Docetaxel Cyclophosphamide - - Compatible in Y(10) CCS(7) CCNS(7) Docetaxel is a CCS drug, while cyclophosphamide is a CCNS drug, which justifies this infusion sequence. Cyclophosphamide is a prodrug, catalyzed directly through cytochrome P450.(11) Docetaxel is also oxidated by cytochrome P450 enzymes, especially by CYP3A4 in the liver.(29) We found a few controversial studies that relate and docetaxel because ifosfamide and cyclophosphamide are similar.(30) Schijvers et al. observed the AUC of ifosfomide and its metabolites were smaller when docetaxel was administered first.(31) A study by Ando et al., suggests that docetaxel can competitively inhibit the biotransformation of the prodrug ifosfamide through the isoenzyme CYP3A4 of cytochrome P450.(32) However, the studies we found present no clear evidence for an administration sequence of these drugs. Trastuzumab + Trastuzumab Paclitaxel - - Compatible in Y(10) paclitaxel CCS(7) Lee et al., observed pre-treatment with trastuzumab resulted in better sensitization of breast cancer cells, i.e., trastuzumab followed by paclitaxel increased the activation and induction of programmed cell death or cell apoptosis.(33) Moreover, due to the possible infusion reaction of the monoclonal antibody, it is recommended that trastuzumab be infused first.(34,35) CCNS: cell-cycle nonspecific; CCS: cell-cycle specific; AUC: area under the curve.

Table 3. Combination of chemotherapeutic agents in which sequence has no ❚❚DISCUSSION effect on efficacy or toxicity There are few studies in the literature evaluating + paclitaxel(36,37) the infusion sequence of antineoplastic drugs in Gemcitabine + docetaxel(38,39) chemotherapy protocols. The definition of more Trastuzumab + pertuzumab(40-42) adequate administration sequences, considering the

einstein (São Paulo). 2018;16(2):1-9 6 Standardization of the infusion sequence of antineoplastic drugs constituent drugs, can help planning of therapeutic Doxorubicin is a (moderate) inhibitor of this same regimens in a more rational way, and thus optimize enzyme. Therefore, CYP inhibitors can reduce the chemotherapy effects on patients, increasing efficacy metabolism of substrates of this pathway, leading to and reducing toxic effects. The main criteria to decreased serum concentration of cyclophosphamide.(12) be considered when defining the ideal order are: Most antineoplastic drugs affect mainly cell division. In pharmacokinetics/pharmacodynamics (including the cell many cases, the antiproliferative action of antineoplastic cycle phase in which the antineoplastic drugs act) and drug drugs is directly in the DNA, resulting in permanent characteristics (vesicant/irritant and incompatibilities). damage and initiating cell apoptosis. A better result Moreover, considering that the main target is cell division, of these antineoplastic drugs can be obtained through the drugs affect all normal tissues in quick division, and the action during the S phase of the cell cycle, when they will probably produce some toxicity, either at high the cell is synthetizing a new DNA.(44) Thus, regarding or low levels.(43) infusion order, if we administer a CCS antineoplastic Based on information related to each drug’s drug before a CCNS agent, we can theoretically expect pharmacokinetics and pharmacodynamics, it is possible a maximization of the effects on cells with a high cell to evaluate antagonism or synergism, in relation to division rate, such as the neoplastic cells. Thus, with an efficacy and safety. The synergistic effect is one of interrupted cell cycle, antineoplastic agents can more the main reasons for using combined chemotherapy. easily act in the DNA. Synergy is defined as an expected additive effect when In addition, the higher the exposure to antineoplastic individual drugs are combined. Antagonism is when drugs, the less stable and more fragile veins become. As the combination of two drugs reduces or nullifies the a consequence, drugs administered last have a higher chance of leakage, regardless of the technique employed. effects of one or both. The combination of folinic acid It is better to administer the vesicant antineoplastic drug (LV) and fluorouracil (5FU) is an example of two drugs first, when the vein is more stable and less irritated. that synergistically act on the same target, yielding Another possibility is using the “sandwich technique”: antitumoral results.(44) Folinic acid increases the effect a non-vesicant antineoplastic drug first, then the vesicant of 5FU by stabilizing the binding of its converted form drug, and lastly another non-vesicant. However, vein (fluorodeoxyuridine acid) to thymidylate synthase, integrity decline due to successive cytotoxic cycles contributing to inhibition of this important enzyme in suggests vesicant drugs are safer when administered DNA repair and replication.(19,20) first.(47) Therefore, administering vesicant drugs first Among the effects related to the pharmacokinetics proves more advantageous and safer for patients. ofthe drugs studied, the most frequent were related The limitations of this study include the fact that, to metabolism/biotransformation and antineoplastic in some cases, the infusion sequence was not clearly medication elimination/excretion. Although some drugs described in the literature, such as: a) the combination are metabolized in their place of absorption, the primary of pamidronate and paclitaxel or docetaxel – the metabolism site is the liver, especially in the P450 infusion order was based on the fact that pamidronate cytochrome enzyme complex. Drugs, food and some can cause nephrotoxicity, which could alter the herbs can induce or inhibit enzymes involved in drug excretion of the other drugs; and b) the combination (45) metabolism. Therefore, it is important to understand of cyclophosphamide and docetaxel, whose data were the role of enzymes and transporters in the metabolism extrapolated from studies with ifosfomide, which belongs of antineoplastic agents and the mechanisms through to the same drug class of cyclophosphamide. which they modulate their expression and activity. Nevertheless, this review showed that many Enzyme inhibition usually leads to an increase infusion sequences have already been well-defined in in the metabolic rate and in the serum concentration the literature, regarding safety, efficacy, prevention of the drug, which can result in increased therapeutic of excessive toxicity or reduced efficacy. Therefore, response or toxicity. Enzyme inhibition effects are understanding the potential drug interactions, medical relatively fast, with their initial effects appearing in teams can minimize risks by prescribing adequate drugs 24 hours. Therefore, patients must be frequently with an appropriate infusion order and monitoring signs monitored.(46) A well-known example of drug interaction of interactions. due to enzyme inhibition is the one between cyclophosphamide and doxorubicin. Cyclophosphamide is a substrate of the enzyme CYP2B6, which means it ❚❚CONCLUSION is a prodrug and requires biotransformation to produce Defining an infusion sequence greatly optimizes its pharmacologically active cytotoxic compounds. treatment. Such sequences must be based on studies

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